Preparations for penicillin therapy



Patented June 22, 1948 2,443,778 PREPARATIONS FOR PENICILLIN THERAPY Monroe 1. Romansky, Silver Spring, Md.

No Drawing. Application April 21, 1947,

Serial No. 742,967

(Granted under the act of March a, 1883, as

Claims.

1 The invention described herein may be manufactured and used by or for the Government for governmental purposes without payment to me of any royalty thereon.

This invention relates to pharmaceutical preparations and more particularly to preparations for penicillin therapy.

The most common method of administering penicillin has been by introducing penicillin in physiologic saline or water through the intramuscular route. This method has not been completely satisfactory since it results-in high blood levels of penicillin which endure for only brief periods of time and necessitate frequent injections. The inconvenience to the patient resulting from this method, as well as the personnel administering the penicillin, is readily apparent. A further disadvantage lies in the fact that penicillin in physiologic saline lacks stability and loses its potency during storage particularly at elevated temperatures. In addition to the foregoing objections this method has acted, in a sense, as a barrier in determining the optimum dose and the period of time necessary for treatment.

Numerous attempts have been made to overcome the foregoing disadvantages, but none of them has been entirely satisfactory. Thus, the intermittent intravenous method also results in transitory high levels and necessitates repeated venipunctures. The constant intravenous procedure, although maintaining a satisfactory level, is'diflicult on the patient and involves the possihiiitv of thrombosis. The constant subcutaneous infusion, the continuous intramuscular drip infusion and the deep infusion into bone marrow, are all inconvenient to the patient and have not been' standardized thus far.

One of the objects of the present invention is to provide more useful pharmaceutical preparations containing penicillin than have been available heretofore.

Another object of the present invention is to provide pharmaceutical preparations containing penicillin which, upon administration, produce satisfactory penicillin blood levels for extended periods.

' A further object of the invention is to provide pharmaceutical preparations containing penicillln which retain their potency for long periods,

amended April 30, 1928: 370 0. G. 757) particularly when stored either at room temperature or elevated temperatures. More specifically, it is an object of this invention to provide a stable pharmaceutical composition containing penicillin in a. substantially anhydrous vehicle of beeswax and highly refined peanut oil.

These objects are accomplished by admixing a warm anhydrous vehicle consisting of beeswax in v peanut oil with either a crystalline penicillin, for example sodium penicillin, or potassium penicillin, or an amorphous penicillin, for example calcium penicillin, whereby there is obtained a pharmaceutical composition comprising these components which is capable of producing satisfactory blood levels of penicillin for long periods and which is more stable than compositions previously available.

In the practice of the invention, a sterilized, highly refined peanut oil is warmed at a temperature of from to C. sterilized U. S. P. bleached beeswax is heated separately at a temperature of from approximately to approximately C. until it forms a clear liquid and the warm peanut oil then is mixed therewith. The melt-blending of the components may be augmented by agitation in a warm container or by means of a mechanical blender. The penicillin derivative is placed in a mechanical blender in as powdery a state as possible, and the clear, liquid beeswax peanut oil mixture added thereto at a temperature of from approximately 50 to 55 C. The penicillin derivative and the wax-oil vehicle are blended until a complete homogeneous suspension is obtained. The composition is willciently liquid after warming to 55-60 C. for 3 to 5 minutes that it can be withdrawn from a rubber stoppered bottle with a No. 18 or 19 gauge needle and after allowing to be cooled to room temperature (approximately 25 C.) can be injected with oil at 17-20 pounds steam for approximately 20 to'30 minutes.

The quantity of beeswax employed is limited principally by viscosity considerations with regard to theiinal product. Eflective results have been obtained with beeswax peanut oil vehicls in which the beeswax content ranges from 0.60 to 4.80 per cent by weight. If the beeswax content is increased substantially beyond the upper limit specified, the compositions obtained are too viscous for practical use, and. furthermore, such increased amounts have been found to have no effect upon prolonging the penicillin action. The preferred beeswax content is from 3.2 to 4.8 per cent by weight and within this range the amount may be varied according to the potency of the penicillin derivative employed. It has been found that higher percentages of beeswax within the range given should be employed withpenicillin derivatives having high potency. In addition to peanut oil, it has been found in practice that oils other than peanut oil. such as sesame oil, olive 011, corn oil, cottonseed oil, and also animal oils, or mineral oil, may be similarly employed to produce a prolonged penicillin action.

It is found in practice that crystalline sodium penicillin or potassium pencillin, and amorphous calcium penicillin act in a similar manner. Penicillin derivatives of any desired potency may be employed, but it is preferred to use the most potent products avail-able in order to produce satisfactory penicillin blood levels for the longest possible periods of time. Compositions of the penicillin derivative in a vehicle of beeswax and proximately 300 milligrams in sufficient beeswax and peanut oil to provide a volume of one cubic centimeter. While it is preferred to employ the a maximum quantity specified, from 175 to 300 milligrams may be used with good results. The maximum quantity of 300 milligrams of the penicillin derivative occupies a volume or approximately 0.2 cubic centimeter and is admixed, therefore, with approximately 0.8 cubic centimeter of beeswax and peanut oil vehicle to provide a volume of one cubic centimeter. It has been found that a relatively constant amount of penicillin is absorbed from each cubic centimeter of the penicillin-beeswax-peanut oil mixture'and by increasing the number of cubic centimeters of the dose only slight additional prolongations were achieved, although a marked increase in the height of the level of penicillin in the blood oc curred.

An extended chemical analysis has been made with regard to the compositionshereinabove described. A calcium penicillin, beeswax and peanut oil mixture was prepared with calcium penicillin having a potency of from 300 to 400 units per milligram employing 3.2 per cent by weight beeswax in the vehicle. One cubic centimeter of this preparations containing a total of 100,000 units produced a maximum penicillin blood level of 0.312 unit per cubic centimeter of blood and assayable levels for approximately ten hours after injection. The presence of penicillin in the urine was detectable for 27 hours after the injection. A calcium penicillin beeswax and peanut oil mixture prepared with calcium penicillin assaying from 600 to 800 units per milligram and 4.0 per cent by weight of beeswax provided a preparation containing 200,000 units per cubic centimeter. An intramuscular injection of one cubic centimeter of this preparation produced a maximum penicillin blood level of 1.25 units per cubic centimeter of blood approximatel four hours after injection and a blood level m excess of 0.039 unit for more than sixteen hours after injection. The presence of penicillin in the urine was detectable for 96 hours after injection.

The following table, Table I, shows penicillin blood levels produced in fifty cases by a single intramuscular injection of 300,000 units of calcium penicillin in 4.8 per cent beeswax by weight in peanut oil contained in 1 cubic centimeter.

TABLE I Penicillin blood levels produced by a single intramuscular injection of 300,000 units of calcium penicillin in 4.8 per cent beeswax by weight in peanut oil contained in 1 cc.

Time Aiter Injection Duration of Case Assayable N 0. Level (0.089

)6 Hr. 4 Br. 8 Hr. 12 Hr. 16 Br. 20 Ht. 2! Hr. Units/cc.)

Units/cc. Units/cc. Units/cc. Units/cc. Units/cc. Units/cc. Units/cc. Hours 0. 156 0. 625 0. 625 0.312 0. 156 0. 078 0.078 24 0. 321 0. 156 0. 078 0. 156 0. 078 0. 156 0. 156 24 0. 625 2. 0. 312 0. 312 0. 156 0. 039 0.039 24 1. 25 1. 25 1. 25 0. 078 0.078 0. 078 0. 078 24 1. 25 1. 25 0. 625 0. 625 0. 156 0. 078 0. 078 24 0. 625 1. 25 1. 25 0. 312 0. 078 0. 039 0. 000 20 1. 25 1. 25 0.312 0. 312 0. 156 0. 078 0. 039 24 1. 25 0. 625 0.312 0.312 0.078 0.078 0.078 24 2. 50 2. 50 0. 625 0. 078 O. 039 0.039 0.000 20 0. 156 0. 625 0. 312 0. 312 0. 156 0. 156 0. 078 24 0. 312 2. 50 2. 50 0. 312 0. 039 0.039 0.039 24 0. 625 2. 50 0. 312 0. 156 i). 078 0.078 0.039 24 0. 312 0. 625 0. 312 0. 078 0. 039 0. 000 0. 000 16 0. 625 1. 25 1. 25 0. 156 0. 039 0. 039 0. 078 24, 0. 625 1. 25 0. 625 0.078 0. 000 0.000 0. 000 12 0. 078 0. 156 0. 078 0. 625 0. 312 0. 078 0. 078 24 0. 312 2. 50 1. 25 0. 078 0. 078 0. 000 0. 000 16 0. 078 0. 078 1. 25 0. 039 0. 039 0. 030 0. 156 24 0. 312 0. 625 0. 625 0. 312 0. 032 0. 039 0. 039 24 0. 156 0. 625 0. 156 0. 156 0. 156 0. 156 0. 312 24 0. 078 0. 078 0. 156 0. 078 0. 000 0. 000 0. 000 12 0. 156 0. 625 0. 312 0. 078 0. 078 0. 07B 0. 039 24 0. 825 0. 625 0. 312 0. 156 0.078 0. 039 0. 039 24 ammo . Team I-Continued Penicillin blood levels roduced by a sincle intramuscular infection of 300,000 units of calcium penicillin in 4.8 per cent beeswax in! weight in peanut all contained in 1 co -Continued Time Alter Inieetlon Duration of Case Assayable No. Level (0039 A Hr. 4 Hr. 8 Hr. 12 Hr. 16 Br. 20 Hr. 24 Hr. Units/cc.)

Units/cc. Unite/cc. Units/cc. Unite/cc. Unite/cc. Unite/cc. Units/cc. Hour: 24 2. 50 1. 25 0.156 0.312 0. 156 0.039 0.000 20 25 0.312 1. 25 0. 156 0. 07B 0.156 0.078 0.039 24 26. 0.312 0.625 1. 25 0. 156 0.078 0. 000 0. 000 16 27 0. 156 0. 625 0. 156 0. 078 0. 078 0. 039 0. 000 20 28- 1. 25 1. 25 1. 25 0. 312 0. 039 0. 000 0. 000 16 0. 156 0. 078 0. 078 0. 078 0. 078 0. 078 0. 039 24 0. 312 1. 25 0. 625 0. 156 0. 078 0. 039 0. 000 20 0. 312 1. 25 0. 625 0. 039 0. 039 0. 078 0. 039 24 0. 312 0. 625 0. 625 0. 078 0. 039 0. 000 0. 000 16 0. 625 1. 25 0. 625 0.078 0. 000 0. 030 0. 000 20 0. 625 1. 25 0. 625 0. 078 0. 039 0. 078 0. 039 24 0. 312 0. 625 0. 312 0. 156 0. 078 0. 039 0. 078 24 0. 312 0. 625 0. 625 0. 312 0. 039 0. 039 0. 078 24 0. 625 0. 625 2. 50 0.078 0. 156 0. 078 0. 039 24 0. 156 0. 156 0. 156 0. 156 0. 039 0. 078 0.078 24 0. 078 0. 156 0.039 0. 156 0. 030 0. 078 0. 156 24 0. 312 1. 25 0. 625 0. 312 0. 039 0. 039 0. 078 24 0. 312 0. 312 .0. 625 0. 625 0. 312 0. 156 0. 078 24 0. 625 1. 25 0. 625 0. 156 0.078 0. 039 0. 039 24 0. 625 0. 625 0. 625 0. 312 0. 156 0. 039 0. 039 24 0. 156 1. 25 0. 312 0. 312 0. 039 0. 039 0. 156 24 0. 3-12 0. 625 0.625 0. 312 0. 156 0.156 0. 156 24 1. 25 l. 25 0. 312 0. 312 0. 07,8 0. 039 0. 039 24 0. 625 0. 625 0. 312 0. 312 0. 078 0. 156 0. 078 24 2. 50 1. 25 0. 156 0. 312 0. 156 0. 039 0. 000 20 0. 625 1. 25 0. 625 0. 078 0. 000 0. 000 0. 000 12 0. 625 1. 25 0. 625 0. 078 0. 039 0. 078 0. 039 24 Out of the aforesaid 50 cases reported, 35 showed assayable levels were retained for more than 24 hours, '7. showed retention of 20 hours, of 16 hours, and 3 of 12 hours, this last being the shortest retention period that was noted. The lowest assayable level, as will be noted irom Table I, is 0.039 unit per cc.

The effect upon maximum penicillin blood levels and the slight prolongation of penicillin action produced by injecting 1, 2 and 3 cubic centimeters of calcium penicillin in 3.2 per cent'beeswax in peanut oil containing 100,000, 200,000 and 300,000 units, respectively, has been demonstrated. A maximum penicillin blood level of 0.312 unit per cubic centimeter of blood was reached from 2 to 4 hours after injection and a level in excess of 0.039 unit was maintained for approximately hours with an injection of one cubic centimeter containing 100,000 units. A two cubic centimeter injection containing 200,000 units produced a maximum penicillin blood level of 1.25 units per cubic centimeter approximately 6 hours after injection and a, blood level in excess of 0.039 unit per cubic centimeter continued for 14 hours. The three cubic centimeter injection containing 300,000 units produced a maximum penicillin blood level of 1.25 units per cubic centimeter approximately 4 hours after injection and a blood level in excess of. 0.039 unit per cubic centimeter induced for only hours.

Similar results are obtainable using the crystalline penicillin salts, e. g., sodium penicillin and potassium penicillin.

Thus, 300,000 units of these crystalline salts were prepared in the same manner as the amorphous calcium penicillin, that is to say, in 4.3 per cent beeswax and peanut oil contained in one cubic centimeter. The viscosity of the resulting mixes containing crystalline sodium penicillin or crystalline potassium penicillin at room temperature is found to be comparable to the corresponding mixes containing amorphous calcium penicillin. In this connection it may be noted that, in carrying out the present invention,

the preferred viscosity of the penicillin in beeswax peanut oil mix is such that the mixture doesnot flow at room temperature C.) since it is the viscose preparations which produce levels of penicillin in the blood which endure for 24 hours. It is found in practice that preparations which are liquid at room temperature usually produce assayable levels for only 12 to 16 hours.

About 500 patients with various types of iniections usually treated with penicillin were given one or. two intramuscular injections of 300,000 units of the crystalline penicillin, beeswax, peanut oil composition of the present invention. About half received the crystalline sodium and the remaining half the crystalline potassium mixture. Most of the patients received a single injection or 300,000 units once in 24 hours. Those who were given two injections daily received them at twelve hour intervals. These patients were both ambulatory and at bed rest. Certain of these individuals received their injection at approximately 4-5 P. M. instead of the usual time of 9 A. M. This is found to be in practice a very important factor in therapy.

Penicillin assays of the blood were carried out at minute and 4 hour intervals for 24 hours or at the 24th hour. This was accomplished on at least 150 patients who received the crystalline sodium and on about an equal number of patients who received the crystalline potassium penicillin beeswax, peanut oil mixture. or that total number, at least 50 had blood levels determined throughout the 24 hours at intervals mentioned above, and the remaining had them at the 24th hour. The usual minimum and maximum blood levels in the first 12 hours have ranged between 0.156 and 2.5 units per cc. The 2.5 unit levels have been found one-half hour after the injection. During the second 12 hours the minimum and maximum levels have been between 0.039 and 0.156. The value of 0.039 unit isan approximate value usually indicating .a level of between 0.039 and 0.078. The results of these studies show that 75 90 per cent of the three hundred patients had a penicillin blood level of 0.039 unit per cc. or higher at the 24th hour after injection, whereas with amorphous calcium penicillin, beeswax. peanut oil mixture approximately 70 to '75 per cent of the patients had levels'ior that period of time.

With the crystalline penicillin salt-containing mixture it was found that those patients who were tested frequently throughout the day and had no assayable level at the 24th hour usually had it at the 20th. Only an occasional patient did not have an assayable level for 20 hours.

The following table, Table II, shows representative results obtained with the penicillin, beeswax, peanut oil mixtures containing crystalline sodium penicillin and crystalline potassium penicillin.

TABLE II Singular intramuscular injection of 300,000 units of crystalline penicillin in 4.8 per cent beeswax in peanut or! contained m 1 cc.

Hours Time of In- Min.

jection l 30 Units per cc. serum l. 25 0. 624 0. 156 0. 039 0. 078 0. 078 1. 25 2. 5 0. 312 0. 156 0. 156 0. 078 0.078 4 p. m 1. 25 0. 624 0. 156 0. 156 0.624 0.624 0. 078 4 p. m 1. 25 0. 624 0.312 0.078 0. 156 0. 156 0.624 1. 25 1. 25 0. 624 0. 156 0. 156 0. 312 0. 039 2. 5 1. 25 0. 624 0. 156 0. 039 0. 039 0. 078 2. 5 1. 25 0. 312 0. 312 0. 156 0.078 0. 039 4p. m. -l.. 2.5 1.25 0.312 0.166 0.078 0.039 0.039 0. 624 0. 624 0. 312 0. 078 0. 039 0. 078 0. 039 5 1. 25 0. 624 0. 156 0. 312 0. 156 0. 078 2. 5 1. 25 0.624 0. 156 0.039 0. 039 0.078 4 p. m 2. 5 l. 25 0. 312 0. 312 0. 156 0.078 0. 039 2. 5 1. 25 0. 312 0.156 0.078 0. 039 0. 039 0. 024 0. 624 0. 312 0. 078 0. 039 0. 078 0. 039 5 1. 25 0. 624 0. 156 0. 312 0. 156 0.078 5 l. 25 0. 624 0. 156 0. 039 0. 078 0. 07B 1. 25 2. 5 0. 312 0. 156 0. 156 0.078 0.078 1. 25 0. 624 0. 156 0. 156 0.624 0.624 0.078 l. 25 0. 624 0. 312 0.078 0. 156 0. 156 0. 624 5 5 1. 25 0. 312 0. 156 0.078 0.078 1. 25 1.25 0. 624 0. 156 0. 156' 0. 312 0. 039 l. 25 0. 624 0. 624 0. 624 0. 312 0. 156 0. 078 1. 25 2. 5 0. 624 0. 312 0. 078 0. 078 0. 624 0. 624 0. 156 0. 078 0. 078 0. 039 0. 6-4 0. 624 0. 156 0. 078 0. 078 0. 039 2. 5 0. use 0. 039 2. 5 0. 156 0. 039

1 Unless otherwise stated, injections given at about 9 a. 111.

With reference to Table II it may be noted that observations relative to the time of injection of the penicillin beeswax peanut oil mixture have T been of considerable interest. In certain instances. it had been noted that when a patient received an injection of the preparation at 9 a. m., there appeared at the 16th to 20th hour (usually 4-5 a. m.) after the injection, a dip in the blood level and subsequently at the 24th hour a rise. This. occurs not only while the patient is sleeping but when there is the least amount of muscle activity. In addition, there would tend to be at this time less absorption of penicillin from the site of the intramuscular injection. Hence, there is a situation, where, simultaneously not only in the least amount of pencillin available the slowedabsorption is occurring. It was desirable, therefore, to check the blood levels when the preparation was given at 4-5 p. m. or later. With this regime, adequate amounts of penicillin are available during the period of least muscle activity, and more penicillin is made available i'or the second 12 hours after the injection the greatest amount of muscle activity is present. A dip in the blood level still occurs about 4-5 a. m. but adequate penicillin is still present. Ac-

- tual observations indicate the desirability that injections of the preparation of the invention should be given in the latter part of the day,

that is, 4 p. m. or later, in order to obtain the optimum penicillin levels. This is particularly true in ambulatory patients since the greatest amount of muscle activity occurs during the day and at a time when more adequate amounts of penicillin will be present in the muscle. For bed patients, it is desirable to utilize the same time (4 p. m. or later) for injection, but there is not as great a diilerence in the blood levels produced probably due to the fact that a bed patient has less muscle activity throughout the day.

It is not clearly understood why more patients have'a level for 24 hours after injection with crystalline penicillin, beeswax, peanut oil mixture than after amorphous penicillin, beeswax, peanut oil mixture, but it seems probable it is because of the greater quantity of the traction penicillin G contained in the crystalline salt. This is indicated by the observation that certain batches of amorphous penicillin, beeswax, peanut oil, which have been very high in fraction G. have produced, in numbers, blood levels comparable to the crystalline penicillin, beeswax, peanut oil composition.

The patients treated with the crystalline material responded as well to this mixture as to the amorphous composition, or aqueous penicillin. Among the patients with syphilis who were treated in the early stage, the spirochete disappearance time and the chancre healing time were comparable to those patients treated with aqueous penicillin or amorphous penicillin, beeswax, peanut oil composition.

The advantageof employing one cubic centimeter doses of the crystalline sodium or potassium penicillin or the non-crystalline calcium penicillin, all of which salts assay the highest possible potency in a vehicle of 4.8 per cent beeswax in peanut oil is apparent from the foregoing, since a daily dose of 300,000 units contained in one cubic centimeter of such a preparation will maintain a penicillin blood level for about 24 hours which is adequate for all but overwhelming infections. Individuals whose weight is pounds or less can be given 3000 units per pound and will maintain adequate penicillin levels in the blood for about 24 hours. For extremely severe infections, 300,000 units in one cubic centimeter can be given at 12 hour intervals to maintain continuously a penicillin level in the blood of from 0.312 to 1.25 units per cubic centimeter of blood. Extremely high penicillin blood levels may be attained by employing two, three and four cubic centimeter intramuscular injections of the penicillin salt in a vehicle of 4.8 per cent by weight beeswax in peanut oil containing a total 01' 600,000, 900,000 and 1,200,000 units, respectively, though the duration of penicillin action is not prolonged materially. Such injections produce maximum penicillin blood levels of from 2.5 to 10 units per cubic centimeter of blood for from 1 to 10 hours after injection and penicillin blood levels of a minimum of 0.078 unit are maintained for over 24 hours after injection. Penicillin may be detected in the urine for approximately 144 hours following such injections.

In this connection, it may be pointed out that using crystalline salts of penicillin, for example sodium penicillin or potassium penicillin, there may be employed an excess of 300,000 units. With these salts no increase in beeswax concentration is required up to 600,000 units or more. The crystalline penicillin salts are stable in powof the invention, therefore,

I composition appears to be In aqueous solution they are no more stable than is amorphous penicillin. The crystalline salts are as stable in the oil-beeswax vehicle as they are in the powdered form.

The pharmaceutical preparations described herein may be employed to treat gonococcic, pneumococcic and well as other infections which respond to penicillin in physiologic saline. The preparations, furthermore, do not cause patients any discomfort, other than a slight soreness present to pressure, and a single injection daily produces a response heretofore attained only by 8 or more in jections a day of penicillin in saline or water. Clinical studies have not revealed gross residual to paipitation in any instance and hematologic studies, including bleeding, clotting and prothrombin time, likewise revealed no adverse effects. Gross and microscopic studies of the tissues at the site of injection show results no different from those found at the site of injection of any medication in oil. The vial containing the penicillin beeswax and peanut oil mixture should be kept for 3 to 5 minutes under the hot water tap at 56 to 60 C. The-preparation is shaken at intervals so that there is thorough warming of all the material. At this time the mixture may be withdrawn with an 18-gauge or larger needle into a Luer-Lok syringe and should be allowed to cool to room temperature prior to injection. It is definitely unnecessary to rewarm the syringe. For intramuscular injection a 20- gauge needle should be utilized. The penicillin beeswax, peanut oil mixture should not'be forced into the 20-gauge needle until the needle is inserted in the muscle, since the mixture occa-. sionally hardens in the needle making it difilcult to inject. Only a completely dry needle and syringe should be used. Disposable cartridges containing 300,000 units in one cubic centimeter of the standard mixture are available, which facilitate the administration of the mixture.

The stability of these preparations is high and they may be maintained at 3"! C. for. at least 9 months without loss of potency, whereas penicillin in physiologic saline or water begins to lose its potency in five days at this temperature. At room temperature, the penicillin salt, beeswax peanut oil mixture of the present invention may be stored for at least a year without deterioration. In addition, no deterioration of the calcium penicillin beeswax and peanut oil mixture occurs for 24 to 36 hours at 56 C. or for 2 hours at 100 C. v The crystalline penicillin salts in beeswax and peanut oil show no deterioration for as long as 128 hours at 100 C. dry heat. The mixtures may be stored in an dered dry form.

staphylococcic infections asbeeswax, ithas also been mentioned that other oils such as com oil, sesame oil, cottonseed oil I claim as new and wish to secure by ice box at room temperature or at a temperature of 37 C. without damage.

The foregoing results indicate that the action of penicillin may be prolonged greatly by intramuscular injection of the penicillin salt, beeswax and peanut oil mixture. It alsohas been found that these mixtures may be administered orally to patients and produce therapeutic levels in the blood as well as satisfactory clinical response.

The function of the beeswax in the present a shielding effect on the penicillin salt employed, inhibiting excessively rapid absorption of the penicillin salt. It is found in practice that the beeswax is a necessary constituent in the present composition since 4 injections of 300,000 units of the penicillin salts in peanut oil without beeswax are found to produce adequate blood levels for only about 6 hours.

' each cubic centimeter-of volume of i and mineral oil may be employed as the vehicle, with whatever variation of the proportion of beeswax that is found necessary to effect the desired prolongation of the penicillin salt. However,

oils derived from animal origins also may beemployed. Generally speaking, an oil derived from any source, which oil has a kinematic viscosity at F. of not more than approximately 42 centistokes, may be employed for the purposes of the present invention.

It will be understood also that the invention is not limited necessarily to the specific penicillin salts herein disclosed, that is, crystalline sodium penicillin, crystalline potassium penicillin and amorphous calcium penicillin, these three components being the commercially available penicillin salts at the present time. However, the data and examples herein given are intended to be exemplary only in character, the invention being directed essentially to the incorporation of an available penicillin salt in the beeswax oil mixture disclosed herein.

It will be apparent, therefore, that the invention is capable of being employed with varying constituents such as, for example, different salts of penicillin and different oil vehicles having the specified viscosity, peanut oil being, however, the preferred vehicle. It is thought to be apparent from the foregoing that the invention is capable of modification as will become apparent to one skilled in the art, as determined by given conditions of use, and that, therefore, it is intended and desired to embrace within the scope of this invention such modifications and changes as may be necessary to adapt it to varying conditions and uses, as defined by the scope of the appended claims.

The present application is a continuation-inpart of my copending application Serial No. 609,316, filed August 6, 1945, now abandoned, for Pharmaceutical preparations and method of making the same.

Having thus described my invention, what 1 letters Patent is:

1. A stable, injectable antibiotic preparation each cubic centimeter of volume of which consists of at least 100,000 units of a water-soluble penicillin salt homogeneously dispersed in a mixture of a sterilized vegetable oil having a kinematic viscosity at 100 F. of not more than 42 centlistokes and beeswax of which the beeswax constitutes about 324.8% by weight, each such cubic centimeter of volume of such preparation having the capacity of maintaining an adequate penicillin blood level for a period of at least 8 hours when injected into a patient as a'single dosage.

2. A stable, injectable antibiotic preparation each cubic centimeter of volume of which consists of approximately 300,000 units of a water-soluble penicillin salt homogeneously dispersed in a-mixture of sterilized peanut the beeswax constitutes about 4.8% by weight, each such cubic centimeter of volume of such preparation having the capacity of maintaining an adequate penicillin blood level for a period of about 24 hours when injected into a patient as a single dosage.

3. A stable, injectable antibiotic preparation which consists of approximately 30 ,000 units of sodium peniciloil and beeswax of which lin homogeneously dispersed in a, mixture of sterilized peanut oil and beeswax of which the beeswax constitutes about 4.8% by weight, each such cubic centimeter of volume of such preparation having the capacity of maintaining an adequate penicillin blood level for a period of about 24 hours when injected into a, patient as a single dosage.

4. A stable, injectable antibiotic preparation each cubic centimeter of volume of which consists of approximately 300,000 units of potassium penicillin homogeneously dispersed in a mixture of sterilized peanut oil and beeswax of which the beeswax constitutes about 4.8% by weight, each such cubic centimeter of volume of such preparation having the capacity of maintaining an adequate penicillin blood level for a period of about 24 hours when injected into a patient as a single dosage.

5. A stable, injectable antibiotic preparation each cubic centimeter of volume of which consists of approximately 300,000 units of calcium penicillin homogeneously dispersed in a mixture of sterilized peanut oil and beeswax of which the beeswax constitutes about 4.8% by weight, each 5 dosage.

MONROE J. ROMANSKY.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,791,878 Strauch' Feb. 10, 1931 15 2,190,183 Friedrich Feb. 13, 1940 OTHER REFERENCES Hobby et al.: Proc. Soc. Exptl. Biol. and Med., June 1942, page 286.

. Code et al.: Amer. J. Physiology, June 1941,

pages P240 and P241; ibid., Proc. Soc. Exptl. Biol. and Med., June 1940, pages 475-477.

New England J. Med., Nov. 15, 1945, page 580. 

